Three esters of N-acyl phenyl isoserine, taxol, taxotere and cephalomanninie have been found to possess significant properties as antitumor agents. This application describes a process for the preparation of N-acyl, N-sulfonyl and N-phosphoryl substituted isoserine esters, in general and to a semi-synthesis for the preparation of taxane derivatives such as taxol, taxotere and other biologically active derivatives involving the use of metal alkoxides and xcex2-lactams, in particular.
The taxane family of terpenes, of which taxol is a member, has attracted considerable interest in both the biological and chemical arts. Taxol is a promising cancer chemotherapeutic agent with a broad spectrum of antileukemic and tumor-inhibiting activity. Taxol has the following structure: 
wherein Ph is phenyl and Ac is acetyl. Because of this promising activity, taxol is currently undergoing clinical trials in both France and the United States.
The supply of taxol for these clinical trials is presently being provided by the bark from Taxus brevifollia (Western Yew). However, taxol is found only in minute quantities in the bark of these slow growing evergreens, causing considerable concern that the limited supply of taxol will not meet the demand. Consequently, chemists in recent years have expended their energies in trying to find a viable synthetic route for the preparation of taxol. So far, the results have not been entirely satisfactory.
One synthetic route that has been proposed is directed to the synthesis of the tetracyclic taxane nucleus from commodity chemicals. A synthesis of the taxol congener taxusin has been reported by Holton, et al. in JACS 110, 6558 (1988). Despite the progress made in this approach, the final total synthesis of taxol is, nevertheless, likely to be a multi-step, tedious, and costly process.
A semi-synthetic approach to the preparation of taxol has been described by Greene, et al. in JACS 110, 5917 (1988), and involves the use of a congener of taxol, 10-deacetyl baccatin III which has the structure of formula II shown below: 
10-deacetyl baccatin III is more readily available than taxol since it can be obtained from the needles of Taxus baccata. According to the method of Greene et al., 10-deacetyl baccatin III is converted to taxol by attachment of the C-10 acetyl group and by attachment of the C-13 xcex2-amido ester side chain through the esterification of the C-13 alcohol with a xcex2-amido carboxylic acid unit. Although this approach requires relatively few steps, the synthesis of the xcex2-amido carboxylic acid unit is a multi-step process which proceeds in low yield, and the coupling reaction is tedious and also proceeds in low yield. However, this coupling reaction is a key step which is required in every contemplated synthesis of taxol or biologically active derivative of taxol, since it has been shown by Wani, et al. in JACS 93, 2325 (1971) that the presence of the xcex2-amido ester side chain at C13 is required for anti-tumor activity.
More recently, it has been reported in Colin et al. U.S. Pat. No. 4,814,470 that taxol derivatives of the formula III below, have an activity significantly greater than that of taxol (I). 
Rxe2x80x2 represents hydrogen or acetyl and one of Rxe2x80x3 and Rxe2x80x3xe2x80x2 represents hydroxy and the other represents tert-butoxy-carbonylamino and their stereoisomeric forms, and mixtures thereof.
According to Colin et al., U.S. Pat. No. 4,418,470, the products of general formula (III) are obtained by the action of the sodium salt of tert-butyl N-chlorocarbamate on a product of general formula: 
in which Rxe2x80x2 denotes an acetyl or 2,2,2-trichloroethoxy-carbonyl radical, followed by the replacement of the 2,2,2-trichloroethoxycarbonyl group or groups by hydrogen. It is reported by Denis et al. in U.S. Pat. No. 4,924,011, however, that this process leads to a mixture of isomers which has to be separated and, as a result, not all the baccatin III or 10-deactylbaccatin III employed for the preparation of the product of general formula (IV) can be converted to a product of general formula (III).
In an effort to improve upon the Colin et al. process, Denis et al. disclose a different process for preparing derivatives of baccatin III or of 10-deactyl-baccatin III of general formula 
in which Rxe2x80x2 denotes hydrogen or acetyl wherein an acid of general formula: 
in which R1 is a hydroxy-protecting group, is condensed with a taxane derivative of general formula: 
in which R2 is an acetyl hydroxy-protecting group and R3 is a hydroxy-protecting group, and the protecting groups R1, R3 and, where appropriate, R2 are then replaced by hydrogen. However, this method employs relatively harsh conditions, proceeds with poor conversion, and provides less than optimal yields.
A major difficulty remaining in the synthesis of taxol and other potential anti-tumor agents is the lack of a readily available method for easy attachment, to the C-13 oxygen, of the chemical unit which provides the xcex2-amido ester side chain. Development of such a process for its attachment in high yield would facilitate the synthesis of taxol as well as related anti-tumor agents having a modified set of nuclear substituents or a modified C-13 side chain. This need has been fulfilled by the discovery of a new, efficient process for attachment, to the C-13 oxygen, of the chemical unit which provides the xcex2-amido ester side chain.
Another major difficulty encountered in the synthesis of taxol is that known processes for the attachment of the xcex2-amido ester side chain at C-13 are generally not sufficiently diastereoselective. Therefore the side chain precursor must be prepared in optically active form to obtain the desired diastereomer during attachment. The process of this invention, however, is highly diastereoselective, thus permitting the use of a racemic mixture of side chain precursor, eliminating the need for the expensive, time-consuming process of separating the precursor into its respective enantiomeric forms. The reaction additionally proceeds at a faster rate than previous processes, thus permitting the use of less side-chain precursor than has been required by such previous processes.
Among the objects of the present invention, therefore, is the provision of a process for the preparation of N-acyl, N-sulfonyl and N-phosphoryl esters of isoserine; the provision of a side chain precursor for the synthesis of taxane derivatives; the provision of a process for the attachment of the side chain precursor in relatively high yield to provide an intermediate which is readily converted to the desired taxane derivative; and the provision of such a process which is highly diastereo-selective.
In accordance with the present invention, a process is provided for the preparation of isoserine esters having the formula 
comprising reacting a xcex2-lactam with a metal alkoxide, the xcex2-lactam having the formula 
and the metal alkoxide having the formula
MOCE1E2E3 
wherein
R1 is xe2x80x94OR6, xe2x80x94SR7, or xe2x80x94NR8R9;
R2 is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl;
R3 and R4 are independently hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, or acyl, provided, however, that R3 and R4 are not both acyl;
R5 is xe2x80x94COR10, xe2x80x94COOR10, xe2x80x94COSR10, xe2x80x94CONR8R10, xe2x80x94SO2R11, or xe2x80x94POR12R13,
R6 is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, hydroxy protecting group, or a functional group which increases the water solubility of the taxane derivative,
R7 is alkyl, alkenyl, alkynyl, aryl, heteroaryl, or sulfhydryl protecting group,
R8 is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl;
R9 is an amino protecting group;
R10 is alkyl, alkenyl, alkynyl, aryl, or heteroaryl,
R11 is alkyl, alkenyl, alkynyl, aryl, heteroaryl, xe2x80x94OR10, or xe2x80x94NR8R14,
R12 and R13 are independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, xe2x80x94OR10, or xe2x80x94NR8R14,
R14 is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl;
E1, E2 and E3 are independently hydrogen, hydrocarbon or cyclic, provided, at least one of E1, E2 and E3 is other than hydrogen. Preferably, two of E1, E2, and E3 together with the carbon to which they are attached comprise a mono- or polycyclic skeleton.
In accordance with another aspect of the present invention, the metal alkoxide and xcex2-lactam are selected so as to provide a process for preparing taxol, taxotere and other biologically active taxane derivatives having the following structural formula: 
wherein
R1-R14 are as previously defined,
R15 and R16 are independently hydrogen, hydroxy, lower alkanoyloxy, alkenoyloxy, alkynoyloxy, aryloyloxy or R15 and R16 together form an oxo;
R17 and R18 are independently hydrogen or lower alkanoyloxy, alkenoyloxy, alkynoyloxy, or aryloyloxy or R17 and R18 together form an oxo;
R19 and R20 are independently hydrogen or hydroxy or lower alkanoyloxy, alkenoyloxy, alkynoyloxy, or aryloyloxy;
R21 and R22 are independently hydrogen or lower alkanoyloxy, alkenoyloxy, alkynoyloxy, or aryloyloxy or R21 and R22 together form an oxo;
R24 is hydrogen or hydroxy or lower alkanoyloxy, alkenoyloxy, alkynoyloxy, or aryloyloxy; or
R23 and R24 together form an oxo or methylene or
R23 and R24 together with the carbon atom to which they are attached form an oxirane ring or
R23 and R22 together with the carbon atom to which they are attached form an oxetane ring;
R25 is hydrogen, hydroxy, or lower alkanoyloxy, alkenoyloxy, alkynoyloxy, or aryloyloxy or
R26 is hydrogen, hydroxy, or lower alkanoyloxy, alkenoyloxy, alkynoyloxy, or aryloyloxy; or R26 and R25 taken together form an oxo; and
R27 is hydrogen, hydroxy or lower alkoxy, alkanoyloxy, alkenoyloxy, alkynoyloxy, or aryloyloxy.
Briefly, therefore, the taxane derivatives are prepared by reacting a xcex2-lactam (2) with a metal alkoxide having the bi-, tri- or tetracyclic taxane nucleus to form a xcex2-amido ester intermediate. The intermediate is then converted to the taxane derivative. xcex2-lactam (2) has the general formula: 
wherein R1-R5 are as previously defined. The metal alkoxide preferably has the tricyclic taxane nucleus corresponding to the general formula: 
wherein M is a metal, and R15-R27 are as previously defined. Most preferably, the metal alkoxide has the tetracyclic taxane nucleus corresponding to metal alkoxide (3) wherein R22 and R23 together form an oxetane ring.
Other objects and features of this invention will be in part apparent and in part pointed out hereinafter.
The present invention is directed to a process for preparing substituted isoserine esters, in general, and taxol, taxotere and other taxane derivatives which are biologically active using xcex2-lactam (2), the structure of which is depicted hereinbelow: 
wherein R1, R2, R3, R4 and R5 are as previously defined.
In accordance with the present invention, R5 of xcex2-lactam (2) is preferably xe2x80x94COR10 with R10 with R10 being aryl, heteroaryl, p-substituted phenyl, or lower alkoxy, and most preferably phenyl, methoxy, ethoxy, tert-butoxy (xe2x80x9cLBuOxe2x80x9d; (CH3)3COxe2x80x94), or 
wherein X is Cl, Br, F, CH3Oxe2x80x94, or NO2xe2x80x94. Preferably R2 and R4 are hydrogen or lower alkyl. R3 is preferably aryl, most preferably, naphthyl, phenyl, 
wherein X is as previously defined, Me is methyl and Ph is phenyl. Preferably, R1 is selected from xe2x80x94OR6, xe2x80x94SR7 or xe2x80x94NR8R9 wherein R6, R7 and R9, are hydroxy, sulfhydryl, and amine protecting groups, respectively, and R8 is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl. Most preferably, R1 is xe2x80x94OR6 wherein R6 is triethylsilyl (xe2x80x9cTESxe2x80x9d), 1-ethoxyethlyl (xe2x80x9cEExe2x80x9d) or 2,2,2-trichloroethoxymethyl.
The xcex2-lactam alkyl groups, either alone or with the various substituents defined hereinabove are preferably lower alkyl containing from one to six carbon atoms in the principal chain and up to 15 carbon atoms. They may be straight or branched chain and include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, aryl, hexyl, and the like.
The xcex2-lactam alkenyl groups, either alone or with the various substituents defined hereinabove are preferably lower alkenyl containing from two to six carbon atoms in the principal chain and up to 15 carbon atoms. They may be straight or branched chain and include ethenyl, propenyl, isopropenyl, butenyl, isobutenyl, aryl, hexenyl, and the like.
The xcex2-lactam alkynyl groups, either alone or with the various substituents defined hereinabove are preferably lower alkynyl containing from two to six carbon atoms in the principal chain and up to 15 carbon atoms. They may be straight or branched chain and include ethynyl, propynyl, butynyl, isobutynyl, aryl, hexynyl, and the like.
The xcex2-lactam aryl moieties described, either alone or with various substituents, contain from 6 to 15 carbon atoms and include phenyl, xcex1-naphthyl or xcex2-naphthyl, etc. Substituents include alkanoxy, protected hydroxy, halogen, alkyl, aryl, alkenyl, acyl, acyloxy, nitro, amino, amido, etc. Phenyl is the more preferred aryl.
As noted above, R1 of xcex2-lactam (2) may be xe2x80x94OR6 with R6 being alkyl, acyl, ethoxyethyl (xe2x80x9cEExe2x80x9d), triethylsilyl (xe2x80x9cTESxe2x80x9d), 2,2,2-trichloroethoxymethyl, or other hydroxyl protecting group such as acetals and ethers, i.e., methoxymethyl (xe2x80x9cMOMxe2x80x9d), benzyloxymethyl; esters, such as acetates; carbonates, such as methyl carbonates; and alkyl and aryl silyl such as triethylsilyl, trimethylsilyl, dimethyl-t-butylsilyl, dimethylarylsilyl, dimethyl-heteroarylsilyl, and triisopropylsilyl, and the like. A variety of protecting groups for the hydroxyl group and the synthesis thereof may be found in xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d by T. W. Greene, John Wiley and Sons, 1981. The hydroxyl protecting group selected should be easily removed under conditions that are sufficiently mild, e.g., in 48% HF, acetonitrile, pyridine, or 0.5% HCl/water/ethanol, and/or zinc, acetic acid so as not to disturb the ester linkage or other substituents of the taxol intermediate. However, R6 is preferably triethylsilyl, 1-ethoxyethyl or 2,2,2-trichloroethoxymethyl, and most preferably triethylsilyl.
Also as noted previously, R7 may be a sulfhydryl protecting group and R9 may be an amine protecting group. Sulfhydryl protecting groups include hemithioacetals such as 1-ethoxyethyl and methoxymethyl, thioesters, or thiocarbonates. Amine protecting groups include carbamates, for example, 2,2,2-trichloroethylcarbamate or tertbutylcarbamate. A variety of sulfhydryl and amine protecting groups may be found in the above-identified text by T. W. Greene.
Since xcex2-lactam (2) has several asymmetric carbons, it is known to those skilled in the art that the compounds of the present invention having asymmetric carbon atoms may exist in diastereomeric, racemic, or optically active forms. All of these forms are contemplated within the scope of this invention. More specifically, the present invention includes enantiomers, diastereomers, racemic mixtures, and other mixtures thereof.
xcex2-lactam (2) can be prepared from readily available materials, as is illustrated in schemes A and B below: 
reagents: (a) triethylamine, CH2Cl2, 25xc2x0 C., 18 h; (b) 4 equiv ceric ammoniun nitrate, CH3CN, xe2x88x9210xc2x0 C., 10 min; (c) KOH, THF, H2O, 0xc2x0 C., 30 min; (d) ethyl vinyl ether, THF, toluene sulfonic acid (cat.), 0xc2x0 C., 1.5 h; (e) n-butyllithium, ether, xe2x88x9278xc2x0 C., 10 min; benzoyl chloride, xe2x88x9278xc2x0 C., 1 h; (f) lithium (diisopropyl amide, THF xe2x88x9278xc2x0 C. to xe2x88x9250xc2x0 C.; (g) lithium hexamethyldisilazide, THF xe2x88x9278xc2x0 C. to 0xc2x0 C.; (h) THF, xe2x88x9278xc2x0 C. to 25xc2x0 C., 12 h.
The starting materials are readily available. In scheme A, xcex1-acetoxy acetyl chloride is prepared from glycolic acid, and, in the presence of a tertiary amine, it cyclocondenses with imines prepared from aldehydes and p-methoxyaniline to give 1-p-methoxyphenyl-3-acyloxy-4-arylazetidin-2-ones. The p-methoxyphenyl group can be readily removed through oxidation with ceric ammonium nitrate, and the acyloxy group can be hydrolyzed under standard conditions familiar to those experienced in the art to provide 3-hydroxy-4-arylazetidin-2-ones. The 3-hydroxyl group is protected with 1-ethoxyethyl, but may be protected with variety of standard protecting groups such as the triethylsilyl group or other trialkyl (or aryl) silyl groups. In Scheme B, ethyl-xcex1-triethylsilyloxyacetate is readily prepared from glycolic acid.
The racemic xcex2-lactams may be resolved into the pure enantiomers prior to protection by recrystallization of the corresponding 2-methoxy-2-(trifluoromethyl) phenylacetic esters. However, the reaction described hereinbelow in which the xcex2-amido ester side chain is attached has the advantage of being highly diastereo-selective, thus permitting the use of a racemic mixture of side chain precursor.
The 3-(1-ethoxyethoxy)-4-phenylazetidin-2-one of scheme A and the 3-(1-triethylsilyloxy)-4-phenylazetidin-2-one of scheme B can be converted to xcex2-lactam (2), by treatment with a base, preferably n-butyllithium, and an acyl chloride, alkylchloroformate, sulfonyl chloride, phosphinyl chloride or phosphoryl chloride at xe2x88x9278xc2x0 C. or below.
The process of the present invention is particularly useful for the esterification of mono- or polycyclic metal alkoxides which are represented by the formula 
in which E1, E2 and the carbon to which they are attached define a carbocyclic and/or heterocyclic skeleton which may be mono- or polycyclic and E3 is hydrogen or hydrocarbon, preferably lower alkyl. Most preferably, the carbocyclic and/or heterocyclic skeleton comprises about 6 to 20 atoms and the hetero atoms are oxygen. The cyclic skeleton may be hydrocarbon and/or heterosubstituted with heterosubstituents including, for example, esters, ethers, amines, alcohols, protected alcohols, carbonyl groups, halogens, oxygen, substituted oxygen or substituted nitrogen.
When the metal alkoxides have the bi-, tri- or tetracyclic taxane nucleus, the process of the present invention may advantageously be used to prepare taxane derivatives, many of which have been found to have significant biological activity. As used herein, a metal alkoxide having the bicyclic taxane nucleus has the carbocyclic skeleton corresponding to rings A and B of metal alkoxide (3): 
M and R15-R27 are as previously defined. A metal alkoxide having the tricyclic taxane nucleus has the carbocyclic skeleton corresponding to rings A, B and C of metal alkoxide (3). A metal alkoxide having the tetracyclic taxane nucleus has carbocyclic rings A, B and C of metal alkoxide (3) and the oxetane ring defined by R22, R23, and the carbons to which they are attached.
Preferably, the metal alkoxide used in the process of the present invention is metal alkoxide (3). Most preferably, R15 is xe2x80x94OT2 or xe2x80x94OCOCH3; R16 is hydrogen; R17 and R18 together form an oxo; R19 is xe2x80x94OT1; R20 and R21 are hydrogen; R22 and R23 together with the carbons to which they are attached form an oxetane ring; R24 is CH3COOxe2x80x94; R25 is PhCOOxe2x80x94; R26 is hydrogen; R27 is hydroxy; and T1 and T2 are independently hydrogen or hydroxy protecting group.
Metal substituent, M, of metal alkoxide (3) is a Group IA, IIA, IIIA, lanthanide or actinide element or a transition, Group IIIA, IVA, VA or VIA metal. Preferably, it is a Group IA, IIA or transition metal, and most preferably, it is lithium, magnesium, sodium, potassium or titantium.
The metal alkoxide alkyl groups, either alone or with the various substituents defined hereinabove are preferably lower alkyl containing from one to six carbon atoms in the principal chain and up to 10 carbon atoms. They may be straight or branched chain and include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, aryl, hexyl, and the like.
The metal alkoxide alkenyl groups, either alone or with the various substituents defined hereinabove are preferably lower alkenyl containing from two to six carbon atoms in the principal chain and up to 10 carbon atoms. They may be straight or branched chain and include ethenyl, propenyl, isopropenyl, butenyl, isobutenyl, aryl, hexenyl, and the like.
The metal alkoxide alkynyl groups, either alone or with the various substituents defined hereinabove are preferably lower alkynyl containing from two to six carbon atoms in the principal chain and up to 10 carbon atoms. They may be straight or branched chain and include ethynyl, propynyl, butynyl, isobutynyl, aryl, hexynyl, and the like.
Exemplary alkanoyloxy include acetate, propionate, butyrate, valerate, isobutyrate and the like. The more preferred alkanoyloxy is acetate.
The metal alkoxide aryl moieties, either alone or with various substituents contain from 6 to 10 carbon atoms and include phenyl, xcex1-naphthyl or xcex2-naphthyl, etc. Substituents include alkanoxy, hydroxy, halogen, alkyl, aryl, alkenyl, acyl, acyloxy, nitro, amino, amido, etc. Phenyl is the more preferred aryl.
Metal alkoxides (3) are prepared by reacting an alcohol having two to four rings of the taxane nucleus and a C-13 hydroxyl group with an organometallic compound in a suitable solvent. Preferably, the alcohol is a derivative of baccatin III or 10-deacetyl baccatin III having the structure 
wherein T1 is a hydroxy protecting group, and Z is xe2x80x94OT2 wherein T2 is acyl, preferably acetyl, or other hydroxy protecting group. Most preferably, the alcohol is a protected baccatin III, in particular, 7-O-triethylsilyl baccatin III (which can be obtained as described by Greene, et al. in JACS 110, 5917 (1988) or by other routes) or 7,10-bis-O-triethylsilyl baccatin III.
As reported in Greene et al., 10-deacetyl baccatin III is converted to 7-O-triethylsilyl-10-deacetyl baccatin III according to the following reaction scheme: 
Under what is reported to be carefully optimized conditions, 10-deacetyl baccatin III is reacted with 20 equivalents of (C2H5)3SiCl at 23xc2x0 C. under an argon atmosphere for 20 hours in the presence of 50 ml of pyridine/mmol of 10-deacetyl baccatin III to provide 7-triethylsilyl-10-deacetyl baccatin III (6a) as a reaction product in 84-86% yield after purification. The reaction product is then acetylated with 5 equivalents of CH3COCl and 25 mL of pyridine/mmol of (6a) at 0xc2x0 C. under an argon atmosphere for 48 hours to provide 86% yield of 7-O-tri-ethylsilyl baccatin III (6b). Greene, et al. in JACS 110, 5917 at 5918 (1988).
Alternatively, 7-triethylsilyl-10-deacetyl baccatin III (6a) can be protected at C-10 oxygen with an acid labile hydroxyl protecting group. For example, treatment of (6a) with n-butyllithium in THF followed by triethylsilyl chloride (1.1 mol equiv.) at 0xc2x0 C. gives 7,10-bis-O-triethylsilyl baccatin III (6c) in 95% yield. Also, (6a) can be converted to 7-O-triethylsilyl-10-(1-ethoxyethyl) baccatin III (6d) in 90% yield by treatment with excess ethyl vinyl ether and a catalytic amount of methane sulfonic acid. These preparations are illustrated in the reaction scheme below. 
7-O-triethylsilyl baccatin III (6b), 7,10-bis-O-triethylsilyl baccatin III (6c), or 7-O-triethylsilyl-10-(1-ethoxyethyl) baccatin III (6d) is reacted with an organometallic compound such as n-butyllithium in a solvent such as tetrahydrofuran (THF), to form the metal alkoxide 13-O-lithium-7-O-triethylsilyl baccatin III (7b) 13-O-lithium-7,10-bis-O-triethylsilyl baccatin III (7c), or 13-O-lithium-7-O-triethylsilyl-10-(1-ethoxyethyl) baccatin III (7d) as shown in the following reaction scheme: 
As illustrated in the following reaction scheme, a suitable metal alkoxide of the present invention such as 13-O-lithium-7-O-triethylsilyl baccatin III derivative (7b, 7c, or 7d) reacts with a xcex2-lactam of the present invention to provide an intermediate (8b, 8c, or 8d) in which the C-7 hydroxyl group is protected with a triethylsilyl or 1-ethoxyethyl group. 
Intermediate compound (8b) readily converts to taxol when R1 is xe2x80x94OR6, R2 and R3 are hydrogen, R4 is phenyl, R5 is benzoyl and R6 is a hydroxy protecting group such as triethylsilyl. Intermediate compound (8c) readily converts to taxotere when R1 is xe2x80x94OR6, R2 and R3 are hydrogen, R4 is phenyl, R5 is tertbutoxycarbonyl and R6 is a hydroxy protecting group such as triethylsilyl. Intermediate compound (8d) readily converts to 10-deacetyl taxol when R1 is xe2x80x94OR6, R2 and R3 are hydrogen, R4 is phenyl, R5 is benzoyl, and R6 is a hydroxy protecting group such as triethylsilyl. Intermediate compounds (8b, 8c and 8d) may be converted to the indicated compounds by hydrolyzing the triethylsilyl and 1-ethoxyethyl groups under mild conditions so as not to disturb the ester linkage or the taxane derivative substituents. 
Other taxane derivatives may readily be prepared by selection of the proper substituents R1-R5 of xcex2-lactam (2) or R15-R27 of metal alkoxide (3). The preparation of such other compounds is illustrated in the examples which follow.
Both the conversion of the alcohol to the metal alkoxide and the ultimate synthesis of the taxol can take place in the same reaction vessel. Preferably, the xcex2-lactam is added to the reaction vessel after formation therein of the metal alkoxide.
The organometallic compound n-butyllithium is preferably used to convert the alcohol to the corresponding metal alkoxide, but other sources of metallic substituent such as lithium diisopropyl amide, other lithium or magnesium amides, ethylmagnesium bromide, methylmagnesium bromide, other organolithium compounds, other organomagnesium compounds, organosodium, organotitanium, organozirconium, organozinc, organocadmium or organopotassium or the corresponding amides may also be used. Organometallic compounds are readily available, or may be prepared by available methods including reduction of organic halides with metal. Lower alkyl halides are preferred. For example, butyl bromide can be reacted with lithium metal in diethyl ether to give a solution of n-butyllithium in the following manner: 
Alternatively, the lithium alkoxide may be induced to undergo exchange with metal halides to form alkoxides of aluminum, boron, cerium, calcium, zirconium or zinc.
Although THF is the preferred solvent for the reaction mixture, other ethereal solvents, such as dimethoxyethane, or aromatic solvents may also be suitable. Certain solvents, including some halogenated solvents and some straight-chain hydrocarbons in which the reactants are too poorly soluble, are not suitable. Other solvents are not appropriate for other reasons. For example, esters are not appropriate for use with certain organometallic compounds such as n-butyllithium due to incompatibility therewith.
Although the reaction scheme disclosed herein is directed to the synthesis of certain taxol derivatives, it can be used with modifications in either the xcex2-lactam or the tetracyclic metal alkoxide. Therefore metal alkoxides other than 13-O-lithium-7-O-triethylsilyl baccatin III may be used to form a taxol intermediate according to the method of this invention. The xcex2-lactam and the tetracyclic metal alkoxide can be derived from natural or unnatural sources, to prepare other synthetic taxols, taxol derivatives, 10-deacetyltaxols, and the enantiomers and diastereomers thereof contemplated within the present invention.
The process of the invention also has the important advantage of being highly diastereoselective. Therefore racemic mixtures of the side chain precursors may be used. Substantial cost savings may be realized because there is no need to resolve racemic xcex2-lactams into their pure enantiomers. Additional cost savings may be realized because less side chain precursor, e.g., 60-70% less, is required relative to prior processes.
The water solubility of compounds of formula (1) may be improved if R1 is xe2x80x94OR6 and R19 is xe2x80x94OT1, and R6 and/or T1 are a functional group which increases solubility, such as xe2x80x94COGCOR1 wherein
G is ethylene, propylene, CHCH, 1,2-cyclohexane, or 1,2-phenylene,
R1=OH base, NR2R3, OR3, SR3, OCH2CONR4R5, OH
R2=hydrogen, methyl
R3=(CH2)nNR6R7; (CH2)nN⊕R6R7R8X1xe2x8ax96
n=1 to 3
R4=hydrogen, lower alkyl containing 1 to 4 carbons
R5=hydrogen, lower alkyl containing 1 to 4 carbons, benzyl, hydroxyethyl, CH2CO2H, dimethylaminoethyl
R6R7=lower alkyl containing 1 or 2 carbons, benzyl or R6 and
R7 together with the nitrogen atom of NR6R7 form the following rings 
R8=lower alkyl containing 1 or 2 carbons, benzyl
X1xe2x8ax96=halide
base=NH3, (HOC2H4)3N, N(CH3)3, CH3N(C2H4OH)2, NH2(CH2)6NH2, N-methylglucamine, NaOH, KOH.
The preparation of compounds in which R6 or T1 is xe2x80x94COGCOR1 is set forth in Hangwitz U.S. Pat. No. 4,942,184 which is incorporated herein by reference.
The following examples illustrate the invention.